Melanin concentrating hormone (MCH) is a cyclic peptide that was first isolated from fish over 15 years ago. In mammals, MCH gene expression is localised to the ventral aspect of the zona inserta and the lateral hypothalamic area (Breton et al., Molecular and Cellular Neurosciences, 1993, vol. 4, 271-284). The latter region of the brain is associated with the control of behaviours such as eating and drinking, with arousal and with motor activity (Baker, B., Trends Endocrinol. Metab., 1994, 5, 120-126). Although the biological activity in mammals has not been fully defined, recent work has indicated that MCH promotes eating and weight gain (U.S. Pat. No. 5,849,708). Thus, MCH and its agonists have been proposed as treatments for anorexia nervosa and weight loss due to AIDS, renal disease, or chemotherapy. Similarly, antagonists of MCH can be used as a treatment for obesity and other disorders characterised by compulsive eating and excessive body weight. MCH projections are found throughout the brain, including the spinal cord, an area important in processing nociception, indicates that agents acting through MCHr1, such as compounds of formula I, will be useful in treating pain.
Two receptors for MCH, MCH receptor 1 (MCHr1) (Shimomura et al., Biochem Biophys Res Commun, 1999, 261, 622-6) and MCH receptor 2 (MCHr2) (Hilo et al., J Biol. Chem., 2001, 276, 20125-9) have been identified in humans, while only one (MCHr1) is present in rodent species (Tan et al., Genomics, 2002, 79, 785-92). In mice lacking MCHr1, there is no increased feeding response to MCH, and a lean phenotype is seen, suggesting that this receptor is responsible for mediating the feeding effect of MCH (Marsh et al., Proc. Natl. Acad. Sci. USA, 2002, 99, 3240-5). In addition, MCHr1 antagonists have been demonstrated to block the feeding effects of MCH (Takekawa et al., Eur. J. Pharmacol., 2002, 438, 129-35), and to reduce body weight & adiposity in diet-induced obese rats (Borowsky et al., Nature Med., 2002, 8, 825-30). The conservation of distribution and sequence of MCHr1 suggest a similar role for this receptor in man and rodent species. Hence, MCHr1 antagonists have been proposed as a treatment for obesity and other disorders characterised by excessive eating and body weight. Also, it has been reported that MCHr1 antagonists exhibit antidepressant and anxiolytic-like effects in rodent tests, suggesting a role for MCHr1 in depression and anxiety as well as in other psychiatric disorders (reviewed in Hervieu, G. J., Expert Opin. Ther. Targets, 2006, 10, 211-229).
WO 2003/033476, WO 2004/092181 and WO 2005/042541 discloses 3-phenyl-thieno-pyrimid-4-one derivatives as MCHr1 antagonists for the treatment of obesity and other diseases.
WO 2005/103039 discloses e.g. 3-(pyridin-3-yl)-thienopyrimid-4-one, 6-(pyrid-3-yl)-thienopyridazin-7-one and 6-(pyridin-3-yl)-thienopyran-7-one derivatives as MCHr1 antagonists for treatment of obesity, anxiety, depression and other diseases.
WO 2005/047293 discloses 3-(pyrrolidin-3-yl)-thienopyrimid-4-one derivatives as MCHr1 antagonists for treatment of obesity, anxiety and depression.
Substituted quinoline analogs, containing a chlorophenyl substituted thienopyrimidinone ring system, are presented as MCHr1 antagonists in Warshakoon, N. C. et al., Bioorganic & Medicinal Chemistry Letters, 2006, doi:10.106/j.bmcl.2006.07.006.
Pyrimidine fused bicyclic metalloproteinase inhibitors are disclosed in WO 2004/014916.
Thienopyrimidin-4-one derivatives are disclosed as angiotensin II receptor blockers in WO 93/03040.
Thienopyrimidin-4-one derivatives are disclosed as MCHr1 antagonists for the treatment of obesity in WO2006/118320.
There is an unmet need for MCHr1 antagonists that are more efficacious, more selective (e.g. vs ion channels), more chemically stable, more soluble, more bioavailable and which produce less side effects than known compounds in this field.